Abstract Diabetic retinopathy (DR) is currently the leading cause of vision loss in working age adults. With the anticipated growth of the diabetic population, the number of visually impaired diabetic people who cannot work or care for themselves will continue to be a major public health concern. Vision loss prevention due to DR requires early diagnosis, regular monitoring, and timely therapeutic intervention. Currently, the unmet clinical needs are the ability to prospectively identify which diabetic individuals will develop DR, progress to vision- threatening stages, or respond favorably to therapy. A generally recognized factor that contributes to the development of vision-threatening pathologies due to DR is retinal hypoxia, which can subsequently impair oxygen metabolism. Maintenance of oxygen metabolism is essential for energy production that is vital for cells to survive and perform visual processing. Inner retinal oxygen metabolism is maintained by the balance of inner retinal oxygen delivery and oxygen extraction fraction. Although the retinal tissue and microvasculature have been extensively studied from an anatomical perspective, there is limited information about alterations in retinal oxygen metabolic function and energy production due to DR. The research proposal will overcome this limitation by an innovative, quantitative, and comprehensive multimodal imaging approach to elucidate alterations in oxygen metabolism and defects in regulatory mechanisms that occur at progressive stages of DR, with application of treatment, and in relation to retinal capillary plexus morphology. The specific aims are to: 1) identify inner retina oxygen-metabolic metrics that are associated with stages of DR and indicative of past glycemic control; 2) determine pre-treatment inner retina oxygen-metabolic metrics that are predictive of treatment outcome; 3) elucidate associations among inner retina oxygen-metabolic metrics, capillary plexus morphology and cell layer thickness at stages of DR. The findings will broaden knowledge of DR pathophysiology, improve diagnostic and prognostic evaluation, and propel search for new preventative and therapeutic interventions. The research study can potentially transform clinical assessment of DR, thereby significantly impacting the quality of life of diabetic people and the cost of caring for visually impaired individuals.